CN106660968A

CN106660968A - Pyrazole derivatives and their use as cannabinoid receptor mediators

Info

Publication number: CN106660968A
Application number: CN201580028788.XA
Authority: CN
Inventors: G·库诺斯; M·艾耶; R·西纳; K·C·赖斯
Original assignee: US Department of Health and Human Services
Current assignee: US Department of Health and Human Services
Priority date: 2014-05-09
Filing date: 2015-05-08
Publication date: 2017-05-10
Anticipated expiration: 2035-05-08
Also published as: AU2019227889A1; WO2015172059A8; CN106660968B; AU2015255765A1; CA2948349A1; HK1232213A1; US20180179163A1; JP2017515899A; JP6762930B2; WO2015172059A1; EP3140288B1; CA2948349C; US10329259B2; AU2019227889B2; EP3140288A1

Abstract

The application relates to cannabinoid receptor mediators, or a pharmaceutically acceptable salt or ester thereof, useful in the treatment of e.g. obesity, diabetes or gout, having a structure of: Formula I or Formula I* wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl; Q is H, hydroxyl, or optionally-substituted alkoxy; R1, R2 , and R3 are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, aminocarbonyl, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, aralkyl, optionally-substituted thiol, or R2 and R3 together with Z form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring; Z is B, N, -CH-, or P; D is -S(O)2- or -C(O)-; and n is 0 to 5. The application also relates to compounds of Formula II, wherein U is Formula (A), Ra is -C(=NH)R1; and Rb is a substituted sulfonyl or a substituted carbonyl.

Description

Pyrazole derivatives and its purposes as Cannabined receptor amboceptor

This application claims the rights and interests of the U.S. Provisional Application of the Application No. 61/991,333 of the submission of on May 9th, 2014, should Application is incorporated by reference in their entirety to herein.

Background technology

Endocannabinoids is lipid signal molecule, and they are in same Cannabined receptor (CB₁And CB₂) on work, recognize And adjust the effect of hemp.CB₁The activation of acceptor can increase appetite, increase the biosynthesis and storage of lipid, suppress pancreas islet The activity of element and leptin, and promote inflammation and fibrillatable, which results in CB₁Receptor antagonist is used to treat obesity and its metabolism simultaneously Send out the development of disease (referred to as metabolic syndrome).It is effective that prototype compound Rimonabant is proved to the treatment of metabolic syndrome , but neurological side effects can be caused, this causes such compound to be recalled from market and has suspended further treatment research.

Brief summary of the invention

In one embodiment, compounds as disclosed herein, or its pharmaceutically acceptable salt or ester, with following Structure：

Wherein X and Y are each independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkanes Base, optionally substituted Heterocyclylalkyl or optionally substituted alkyl；

Q is H, hydroxyl or optionally substituted alkoxyl；

R¹, R²And R³It is each independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, nitre Base, hydroxyl, optionally substituted alkoxyl, amino, amino carbonyl, optionally substituted sulfonyl, optionally substituted aryl, optionally take The heteroaryl in generation, optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono Base, optionally substituted phosphinyl, aralkyl, optionally substituted mercaptan, or R²And R³Optionally substituted cycloalkyl is formed together with Z Ring or optionally substituted heterocycloalkyl ring；

Z is B, N ,-CH- or P；

D is-S (O)₂- or-C (O)-；With

N is 0-5.

In further embodiment, compounds as disclosed herein, or its pharmaceutically acceptable salt or ester, have Having structure：

Q is H, hydroxyl or optionally substituted alkoxyl；With

U is

Wherein R^a- C (=NH) R¹, wherein R¹H, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, Nitro, hydroxyl, optionally substituted alkoxyl, amino, amino carbonyl, optionally substituted sulfonyl, optionally substituted aryl, optionally Substituted heteroaryl, optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono Base or optionally substituted phosphinyl；With

R^bIt is a substituted sulphonyl or substituted carbonyl.

In further embodiment, disclosed herein is a kind of compound, or its pharmaceutically acceptable salt or ester, its Including (i) CB₁Receptor-mediated support, and (ii) one second treatment support.

In further embodiment, disclosed herein is a kind of pharmaceutical composition, the pharmaceutical composition includes this paper institutes Disclosed compound, and at least one pharmaceutically acceptable additive.

There is disclosed herein the compounds as disclosed herein of the therapeutic dose including unit dosage form, and at least one medicine Acceptable additive on.

In further embodiment, disclosed herein is it is a kind of for experimenter for treat obesity, diabetes, Non-alcoholic and alcoholic fatty liver disease, the method for obesity symbiosis disease such as artery sclerosis heart disease or gout, including The compounds as disclosed herein of therapeutically effective amount is applied to subject in need.

In further embodiment, disclosed herein is it is a kind of for subject's fibrillatable or the method for liver cancer, Including the compounds as disclosed herein that effective dose is applied to subject in need.

In further embodiment, disclosed herein is a kind of prevention or reverse adipose tissue deposition for experimenter Method, including to subject in need apply effective dose compounds as disclosed herein.

According to the detailed description to several embodiments carried out below with reference to accompanying drawing, content described previously herein will be more Plus it is apparent.

The brief description of accompanying drawing

Fig. 1 describes an embodiment of the general synthetic method for preparing compounds as disclosed herein.

Fig. 2 describes a further embodiment of the general synthetic method for preparing compounds as disclosed herein.

Describe in detail

Term

Be to the following explanation of term and method in order to preferably describe the compound of this paper, composition and method, and Instruct those skilled in the art practice present invention.It is understood that term used in the present invention is specific merely for description The purpose of embodiment and embodiment, rather than it is intended as any restriction.

" acyl group " refers to the group with-C (O) R structures, and wherein R can be for example optionally substituted alkyl, optionally substituted Aryl or optionally substituted heteroaryl." lower acyl " group refers to that those contain the group of 1-6 carbon atom.For example, acyl Base group can be (C₁-C₆) alkanoyl, such as acetyl group, propiono or bytyry.

" acyloxy " refers to the group with-OC (O) R structures, and wherein R can be for example optionally substituted alkyl, optionally Substituted aryl or optionally substituted heteroaryl." low-grade acyloxy " group contains 1-6 carbon atom.For example, alkanoyl can be with It is (C₂-C₆) alkanoyloxy, such as acetoxyl group, propionyloxy, butyryl acyloxy, isobutyl acyloxy, valeryl epoxide or hexanoyl oxygen Base.

" administration " used herein includes from another people being applied to experimenter or experimenter applies self.

Term " aliphatic " is defined to include alkyl, thiazolinyl, alkynyl, haloalkyl and cycloalkyl." lower aliphatic " base Group is branched or non-branching the aliphatic group with 1-10 carbon atom.

" alkane diyl ", " cycloalkanes diyl ", " aryl diyl ", " alkylaryl diyl " are referred to from aliphatic, cycloaliphatic, virtue Divalent group derived from base and alkylaryl hydrocarbons.

" thiazolinyl " refers to ring-type, the branched or straight chain group only containing carbon and hydrogen, and including can with or cannot be coupled One or more double bonds.Thiazolinyl can be substituted or unsubstituted." low-grade alkenyl " group contains 1-6 carbon atom. (C₂-C₆) thiazolinyl can be such as vinyl, pi-allyl, 1- acrylic, 2- acrylic, 1- cyclobutenyls, 2- cyclobutenyls, 3- butylene Base, 1- pentenyls, 2- pentenyls, 3- pentenyls, 4- pentenyls, 1- hexenyls, 2- hexenyls, 3- hexenyls, 4- hexenyls or 5- hexenyls.

Term " alkoxyl " refers to straight chain, branched or ring-type hydrocarbon structure and combinations thereof, including 1-20 carbon atom, preferably 1-8 carbon atom (referred to as " lower alkoxy "), more preferably 1-4 carbon atom, and these carbon atoms are wrapped at tie point Include oxygen atom.One example of " alkoxy base " is represented that wherein R can be alkyl by chemical formula-OR, optionally with thiazolinyl, Alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl, alkoxyl or heterocycloalkyl replace.Suitable alkoxyl includes first Epoxide, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, ring propoxyl group, ring Hexyloxy, amoxy, 3- amoxys or hexyloxy etc..

" alkoxy carbonyl " refers to the carbonyl that alkoxyl replaces, and-C (O) OR, wherein R represents optionally substituted alkyl, virtue Base, aralkyl, cycloalkyl, cycloalkyl-alkyl or similar part.(C₁-C₆) alkoxy carbonyl can be such as methoxycarbonyl group, second Oxygen carbonyl, propylene carbonyl oxygen, butyloxycarbonyl, penta oxygen carbonyl or own oxygen carbonyl.

Term " alkyl " refers to the saturated hydrocarbons group of branched or non-branching 1-24 carbon atom, such as methyl, ethyl, just Propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, amyl group, hexyl, heptyl, octyl group, decyl, myristyl, cetyl, Eicosyl, tetracosyl etc.." low alkyl group " group refers to that the saturation of 1-6 carbon atom is branched or non-branching hydrocarbon.It is preferred that Alkyl group there is 1-4 carbon atom.Alkyl group can be " replacement alkyl ", and wherein one or more hydrogen atoms are following Substituent replaces, such as halogen, cycloalkyl, alkoxyl, amino, hydroxyl, aryl, thiazolinyl or carboxyl.For example, low alkyl group or (C₁- C₆) alkyl can be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, amyl group, 3- amyl groups or hexyl；(C₃- C₆) cycloalkyl can be cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；(C₃-C₆) cycloalkyl (C₁-C₆) alkyl can be ring third Ylmethyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, 2- cyclopropylethyls, 2- CYCLOBUTYLETHYLs, 2- cyclopenta second Base or 2- cyclohexyl-ethyls；Halo (C₁-C₆) alkyl can be iodomethyl, bromomethyl, chloromethyl, methyl fluoride, trifluoromethyl, 2- Chloroethyl, 2- fluoro ethyls, 2,2,2- trifluoroethyls or pentafluoroethyl group；Or hydroxyl (C₁-C₆) alkyl can be methylol, 1- hydroxyl second Base, 2- ethoxys, 1- hydroxypropyls, 2- hydroxypropyls, 3- hydroxypropyls, 1- hydroxyl butyl, 4- hydroxyl butyl, 1- hydroxyl amyl groups, 5- hydroxyl amyl groups, 1- Hydroxyl hexyl or 6- hydroxyl hexyls.

" alkynyl " refers to ring-type, the branched or straight chain group only containing carbon and hydrogen, unless otherwise noted, the carbon for usually containing Atomicity is 1-12, and including one or more three keys.Alkynyl can be substituted or unsubstituted." low-grade alkynyl " group Refer to the group containing 2-6 carbon atom.(C₂-C₆) alkynyl for example can be acetenyl, 1- propinyls, 2-propynyl, 1- butine Base, 2- butynyls, 3- butynyls, 1- pentynyls, valerylene base, 3- pentynyls, 4- pentynyls, 1- hexin bases, 2- hexin bases, 3- Hexin base, 4- hexin bases or 5- hexin bases.

Term " amine " or " amino " refer to the group with-NRR' chemical formulas, and wherein R and R' can be independently hydrogen or alkane Base, thiazolinyl, alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl or heterocycloalkyl.For example, " alkyl amino " or " alkyl Change (alkylated) amino "-NRR' is referred to, at least one of wherein R or R' is alkyl.

Term " aminoalkyl " refers to alkyl group defined above, and wherein at least one hydrogen atom is replaced by amino group (for example ,-CH₂-NH₂)。

Carbonyl (carbamoyl) group that " amino carbonyl " alone or in combination replaces all referring to amino, wherein amino base Group can optionally be single or double replacement, such as use alkyl, aryl, aralkyl, cycloalkyl, cycloalkyl-alkyl, alkanoyl, alcoxyl Base carbonyl, aromatic alkoxy carbonyl etc. replace.Aminocarbonyl group can be-N (R)-C (O)-R (wherein, R be substituted radical or H).Suitable aminocarbonyl group is acetylamino.

Term " acid amides " or " acylamino- " are represented that wherein R and R' can be independently hydrogen, alkane by chemical formula-C (O) NRR' Base, thiazolinyl, alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl or heterocycloalkyl.

" analog " refers to that for example homologue is (in chemical constitution different from the molecule of parent compound in chemical constitution Or on the increment of quality it is different, such as it is different in the length of alkyl chain, or including one or more isotope), molecule fragment, Difference is the structure of one or more functional groups, or the change in terms of ionization.Analog is not necessarily from parent chemical combination Thing synthesis.Derivative is from molecule derived from foundation structure.

" animal " refers to many cells vertebrate organism living, and the category includes such as mammal and birds.Term Mammal includes the mankind and non-human mammal.Similarly, term " experimenter " includes the mankind and nonhuman subjects, bag Include birds and non-human mammal, such as non-human primate, companion animals (such as dog and cat), livestock (such as pig, sheep, Ox), and non-performing animal, such as big cat.No matter which stage of the organism in life cycle, term subject All it is applicable.Therefore, term subject is applied to the organism in uterus or in ovum, and it is (that is, biological that this depends on organism Such as body is mammal or birds, domestic or wild chicken).

Term " aralkyl " refers to that aromatic yl group instead of the alkyl group of a hydrogen atom of alkyl group.Aralkyl One example is benzyl.

" aryl " refers to that the monovalence with monocyclic (for example, phenyl) or multiple condensed ring (for example, naphthyl or anthryl) is unsaturated Aromatic carbocyclic radical, it is optionally substituted or unsubstituted." heteroaryl " is defined as at least one and is integrated into Heteroatomic aromatic group in aromatic group ring.Heteroatomic example is included but is not limited to：Nitrogen, oxygen, sulphur and phosphorus.Heteroaryl bag Include but be not limited to：Pyridine radicals, pyrazinyl, pyrimidine radicals, pyrrole radicals, pyrazolyl, imidazole radicals, thiazolyl, oxazolyl, isoxazolyl, Thiadiazolyl group, oxadiazoles base, thienyl, furyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, quinoxaline Base etc..Aryl or heteroaryl groups can be by one or more substituent groups, including but not limited to, alkyl, alkynyl, thiazolinyl, virtue Base, halide, nitro, amino, ester, ketone, aldehyde, hydroxyl, carboxylic acid or alkoxyl, or aryl or heteroaryl can be unsubstituted 's.

" aryloxy group " or " heteroaryloxy " refers to the group of chemical formula-OAr, and wherein Ar is respectively aryl or heteroaryl.

" carbonyl " refers to-C (O).

Term " carboxylic acid " or " carboxyl " refer to group-COO^-Or-COOH.Carboxyl can form carboxylic acid." substituted carboxyl " Refer to that-COOR, wherein R are alkyl, thiazolinyl, alkynyl, aryl, aralkyl, cycloalkyl, haloalkyl or heterocyclic radical.For example, replace Carboxyl can be carboxylate or its salt (such as carboxylate).

Term " common use (co-administration) " or " common use (co-administering) " are referred to Compounds as disclosed herein is applied together with least one other therapeutic agents or diagnosticum in the same usual time cycle, and Need not apply on same precise moments (although common use is included on same precise moments applying).Therefore, apply jointly With can be in same day or not on the same day, or in same week or in different weeks.

Term " cycloalkyl " refers to the non-aromatic carbon-based ring being made up of at least 3 carbon atoms.The example of cycloalkyl include but It is not limited to, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..Term " heterocycloalkyl " refers to cycloalkyl defined above, At least one carbon atom of the wherein ring is exchanged for heteroatoms, such as but not limited to, nitrogen, oxygen, sulphur or phosphorus.

Term " ester " refers to the part containing carboxylic group, and wherein hydrogen atom is by such as C_1-6Alkyl group (" carboxyl C_1-6Alkane Base " or " Arrcostab "), aryl or aralkyl group (" aryl ester " or " aralkyl ester ") etc. substitutes.CO₂C_1-3Alkyl group is Preferably, such as methyl ester (CO₂Me), ethyl ester (CO₂) and propyl diester (CO Et₂Pr), and including their reverse ester (example Such as-OCOMe ,-OCOEt and-OCOPr).

Term " haloalkyl (halogenated alkyl) " or " haloalkyl (haloalkyl group) " refer to base The alkyl that one or more hydrogen atoms are replaced by halogen (F, Cl, Br, I) in group.

Term " hydroxyl " is represented by chemical formula-OH.

Term " hydroxy alkyl " refers to the alkyl that at least one hydrogen atom is optionally substituted by a hydroxyl group.Term " alkoxyalkyl " is determined Justice is alkyl group, and wherein at least one hydrogen atom is replaced by above-mentioned alkoxy base.

" suppression " refers to the development in an all-round way for suppressing disease or illness." suppression " also refers in any quantity relative to tester Or qualitative biologically active or combination decay.

" N- heterocycles " or " N- heterocycles " refers to single or double ring or loop systems, and it includes at least one nitrogen heteroatom.Should Ring or loop systems generally include the 1-9 carbon atom in addition to hetero atom and can be saturation, undersaturated or aromatics (bag Include false aromatics (pseudoaromatic)).Term " false aromatics " refers to loop systems, and the loop systems are not strict aromatics, but It is stable by means of the means of electron delocalization, and shows the behavior of similar aromatic ring.Aromatics includes false aromatic ring systems, Such as pyrroles's basic ring.

The example of the N- heterocycles of 5 membered monocyclic ring includes pyrrole radicals, H- pyrrole radicals, pyrrolinyl, pyrrolidinyl, oxazolyl, evil Di azoly (including 1,2,3 and 1,2,4 oxadiazoles bases), isoxazolyl, furan a word used for translation base (furazanyl), thiazolyl, isothiazole, pyrrole Azoles, pyrazolinyl, pyrazolidinyl, imidazole radicals, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazole radical, thiophene Di azoly (including 1,2,3 and 1,3,4 thiadiazolyl groups) and dithiazole base.The example of the N- heterocycles of 6 unit monocycles includes pyridine radicals, phonetic Piperidinyl, pyridazinyl, pyrazinyl, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl and triazine radical.The heterocycle can optionally by Extensive substituent replaces, preferred C_1-6Alkyl, C_1-6Alkoxyl, C_2-6Thiazolinyl, C_2-6Alkynyl, halogen, hydroxyl, mercaptan, fluoroform Base, amino, cyano group or single or double (C_1-6Alkyl) amino.N- heterocyclic groups can be fused on carbocyclic ring, for example phenyl, naphthyl, Indenyl, azulenyl (azulenyl), fluorenyl and anthryl.

8th, the example of the heterocycle of 9 and 10 membered bicyclics includes 1H thienos [2,3-c] pyrazolyl, indyl, isoindolyl, benzene And oxazolyl, benzothiazolyl, benzo isoxazolyl, benzisothiazole, benzimidazole, indazolyl, isoquinolyl, quinolyl, Quinoxalinyl, purine radicals, cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, phentriazine base etc..These heterocycles are optionally It is substituted, such as C_1-6Alkyl, C_1-6Alkoxyl, C_2-6Thiazolinyl, C_2-6Alkynyl, halogen, hydroxyl, mercaptan, trifluoromethyl, amino, cyanogen Base or single or double (C_1-6Alkyl) amino.Unless otherwise defined, optionally substituted N- heterocycles include that pyridiniujm and suitable ring nitrogen are former The N- oxide forms of son.

Term " experimenter " includes the mankind and nonhuman subjects, including birds and non-human mammal, such as inhuman spirit Long class animal, such as companion animals (such as dog and cat), livestock (such as pig, sheep, ox) and non-performing animal, big cat.Nothing By which stage of the organism in life cycle, term subject is all applicable.Therefore, term subject is applied in son Organism in utero or in ovum, this depends on organism such as (that is, organism is mammal or birds, domestic or wild Raw chicken).

" substituted " or " replacement " to refer to and change the one of a molecule or R- groups with one or more other R- groups Individual hydrogen atom.Unless otherwise defined, as the term is employed herein " optionally substituted " or " optional substituent " refer to can with or Cannot be by further with 1,2,3,4 or the group of more substituent groups, preferably 1,2 or 3, more preferably 1 or 2.It is optional Substituent be such as C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_3-8Cycloalkyl, hydroxyl, oxo (oxo), C_1-6Alkoxyl, fragrant oxygen Base, C_1-6Alkoxy aryl, halogen, C_1-6Alkyl halide is (such as CF₃And CHF₂)、C_1-6Alkoxyl halogen is (such as OCF₃And OCHF₂), carboxylic Base, ester, cyano group, nitro, amino, substituted-amino, disubstituted amido, acyl group, ketone, acid amides, aminoacyl, replace acid amides, two Substituted acid amides, mercaptan, alkylthio group, thio, sulfate, sulfonate, sulfinyl, sulfinyl, sulfonyl, the replacement of replacement Sulfonyl, sulfonamide, replace sulfonamide, dibasic sulfonamide, aryl, virtue C_1-6Alkyl, heterocyclic radical and heteroaryl, its In each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl and heterocyclic radical and the group containing them can be by further optionally substituted. In the case of N- heterocycles, optional substituent can also be including but not limited to：C_1-6Alkyl, i.e. N-C_1-3Alkyl, more preferably first Base, particularly N- methyl.

" sulfinyl " refers to group-S (=O) H.

Term " substituted sulfinyl " or " sulfoxide " refer to sulfinyl group, and wherein hydrogen atom is by such as C_1-6Alkyl Group (" C_1-6Alkyl sulphinyl " or " C_1-6Alkyl sulfoxide "), aryl (" aryl sulfonyl kia "), (" aralkyl is sub- for aralkyl Sulfonyl ") etc. replace.C_1-3Alkylsulfinyl radicals are preferred, such as-SO methyl ,-SO ethyls and-SO propyl group.

Term " sulfonyl " refers to group-SO₂H。

Term " substituted sulfonyl " refers to sulphonyl groups, and wherein hydrogen atom is by such as C_1-6Alkyl group (" sulfonyl C_1-6Alkyl "), aryl (" aryl sulfonyl "), aralkyl (" arylalkyl sulfonyl "), heteroaryl, cycloalkyl, Heterocyclylalkyl etc. Replace.Sulfonyl C_1-3Alkyl group be it is preferred, for example ,-SO₂Me、-SO₂Et、-SO₂Pr。

Term " sulfonamido " or " sulfonamide " refer to group-SO₂NH₂。

" therapeutically effective amount " refers to the particular agent that be enough to that desired effects are realized on experimenter with the agent treatment Consumption.Ideally, the therapeutically effective amount of medicament be enough to suppress or treat disease or illness, without causing experimenter's Substantial cytotoxic is acted on.The therapeutically effective amount of medicament depends on treated experimenter, the order of severity of pain and controls Treat the method for application of composition.

" mercaptan " refers to group-SH.

Term " substituted mercaptan " refers to thiol group, and wherein hydrogen atom is by such as C_1-6Alkyl group ("-S (C_1-6Alkane Base) "), aryl ("-S (aryl) ") or aralkyl ("-S (alkyl) (aryl) ") etc. replace.(C₁-C₆) alkylthio group for example can be with first Sulfenyl, ethylmercapto group, rosickyite base, isopropyisulfanyl, butylthio, isobutylthio, penta sulfenyl or own sulfenyl.

" treatment " refers to a kind of therapeutic intervention, and it mitigates the S or S of disease or illness after starting to develop, Or the purpose for pointing out in the risk for reducing pathology or ongoing disease or the seriousness for reducing pathology or illness, to not showing Disease signs, or the experimenter of early indication is only shown, apply compound or composition.As used herein, with reference to disease Or illness, term " mitigation " refers to the beneficial effect of any observable treatment.Can be by, for example, the clinic of a certain disease Delay of the symptom on easy infection experimenter, reduces the order of severity of the part or all of clinical symptoms of a certain disease, disease Progress is relatively slow, the holistic health of experimenter or the lifting of happiness, or art-recognized other parameters, it was demonstrated that beneficial effect, These are all clear and definite for specified disease.Phrase " treatment disease " is referred to and suppresses the fully developed of disease, for example, is in Suffer from the experimenter in such as diabetes risk." prevention " disease or illness refer to preventative administration composition to not showing disease Sick body is levied, or only shows the experimenter of early indication, to reduce the risk of pathology or ongoing disease, or reduces pathology or disease The seriousness of disease.In some embodiments disclosed herein, therapeutic scheme suppresses the food intake of experimenter or body weight to increase Plus.In some embodiments disclosed herein, therapeutic scheme suppresses the fiber of experimenter to form or reverse insulin resistance.

" pharmaceutical composition " is a kind of composition, including disclosed in one or more of a certain amount of (such as UD) Compound, and one or more nontoxic pharmaceutically acceptable additive, including carrier, diluent and/or adjuvant, and optionally Other bioactive ingredients.This pharmaceutical composition can be prepared by the drug preparation technique of standard, such as Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,PA(19th Edition) disclosure.

Term " pharmaceutically acceptable salt or ester " refers to the salt or ester being prepared by a conventional method, including salt, for example, nothing Machine acid and organic acid, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, malic acid, acetic acid, grass Acid, tartaric acid, citric acid, lactic acid, fumaric acid, butanedioic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid etc..In mesh In front disclosed compound, " pharmaceutically acceptable salt " also include by cation for example sodium, potassium, aluminium, calcium, lithium, magnesium, zinc and Alkali, such as ammonia, ethylenediamine, N- methyl-glutamines, lysine, arginine, ornithine, choline, N, N'- dibenzyl-ethylenediamins, Chloroprocanine, diethanol amine, procaine, N- benzyl-1-phenylethylamines, diethylamine, piperazine, three (methylol) aminomethanes, hydrogen-oxygen Change the salt that tetramethylammonium is formed.These salt can be prepared by standard method, such as by free acid and appropriate organic base or inorganic It is prepared by alkali reaction.Any chemical compound addressed in this manual can be applied optionally as pharmaceutically acceptable salt With." pharmaceutically acceptable salt " is also including free acid, alkali and zwitterionic form.Suitable pharmaceutically acceptable salt Description can be in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH finds in (2002).When compounds as disclosed herein includes acidic functionality such as carboxylic group, then for carboxyl base Suitable pharmaceutically acceptable cation pair is also well known by persons skilled in the art, including alkali, alkaline earth, ammonium, season for group Ammonium cation etc..This kind of salt is well known by persons skilled in the art.Other examples of " pharmaceutically acceptable salt " are shown in Berge et al.,J.Pharm.Sci.66:1(1977)。

" pharmaceutically acceptable ester " includes those esters derived from above-claimed cpd, and they are modified into can include carboxylic Base group.In vivo hydrolyzable ester is a kind of can to hydrolyze to produce the ester of parent acid or alcohol in human body or animal body.Generation The ester of table includes carboxylate, and wherein the non-carbonyl moiety of the carboxylic moiety of ester group is selected from straight chain or branched-alkyl (for example, first Base, n-propyl, the tert-butyl group or normal-butyl), cycloalkyl, alkoxyalkyl (for example, methoxy), aralkyl (such as benzyl Base), aryloxy alkyl (for example, phenoxymethyl), aryl (for example, phenyl, optionally by such as halogen, C_1-4Alkyl or C_1-4Alkane Epoxide or amino replace)；Sulphonic acid ester, such as alkyl or arylalkyl sulfonyl (for example, mesyl)；Or amino-acid ester (for example, L- Valyl base or L- isoleucyl-s)." pharmaceutically acceptable ester " also includes inorganic ester, such as mono-, di- or triguaiacyl phosphate.At this In a little esters, unless otherwise stated, all of moieties all advantageously contain 1-18 carbon atom, particularly 1-6 carbon atom, More particularly 1-4 carbon atom.In these esters, all of cycloalkyl moiety all advantageously contains 3-6 carbon atom.At these In ester, all of aryl moiety all advantageously comprises a phenyl group, preferably as carbocylic radical defined above (carbocycylyl) equally it is substituted.Therefore pharmaceutically acceptable ester includes C₁-C₂₂Fatty acid ester, such as acetyl group, uncle The straight chain or branched insatiable hunger and/or Ω -6 monounsaturated fatty acids of butyl or length, such as palmityl, stearoyl etc..Optional virtue Base or heteroaryl base ester include benzoyl, pyridylcarboxamide base (pyridylmethyloyl) etc., and either of which therein is Can be substituted, carbocylic radical definition described above.Other pharmaceutically acceptable ester includes aliphatic L-amino acids ester, such as bright Aminoacyl, isoleucyl-, and particularly valyl base.

It is that, for treating, the counter ion counterionsl gegenions of the salt of compound also should be pharmaceutically acceptable.However, not being pharmaceutically may be used The salt of the bronsted lowry acids and bases bronsted lowry of acceptance it is possible to locate that purposes, for example, for preparing or purifying pharmaceutically acceptable compound.

Pharmaceutically acceptable bronsted lowry acids and bases bronsted lowry addition salts mentioned above refer to the nontoxic acid with therapeutic activity and Base addition salts, and the compound of this paper can form these salt.Pharmaceutically acceptable acid-addition salts can be conveniently by with conjunction Suitable acid treatment alkali and obtain.Suitable acid includes, such as inorganic acid such as halogen acids, such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, Phosphoric acid and similar acid；Or organic acid, for example acetic acid, propionic acid, hydroxyl, lactic acid, pyruvic acid, oxalic acid (i.e. ethanedioic acid), malonic acid, Butanedioic acid (i.e. succinic acid), maleic acid, fumaric acid, malic acid (i.e. hydroxysuccinic acid), tartaric acid, citric acid, methanesulfonic acid, second sulphur Not acid and the similar acid of acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, cyclohexane sulfamic acid, salicylic acid, PAS, handkerchief.On the contrary Ground, the salt can be converted into free alkali form by using suitable alkali process.

Compound containing acid proton can also change into the nontoxic of them by using suitable organic base and inorganic base Metal or amine addition salts form.Suitable base salt forms include, such as ammonium salt, alkali and alkali salt, such as lithium, sodium, potassium, Magnesium, calcium salt etc., and the salt of organic base, such as benzyl star, N- methyl-D-glucosamines, Kazakhstan amine salt, and the salt of amino acid, such as essence Propylhomoserin, lysine etc..

The term " addition salts " being used above also includes the solvate that compound as herein described can be formed.These are molten Agent compound such as hydrate, alcoholates etc..

The term " quaternary amine " being used above refers to quaternary ammonium salt, they can by the basic nitrogen of compound Jing compounds with it is suitable Quaternizing agent reacts and is formed, and quaternizing agent is, such as optionally substituted alkyl halide, aryl halide or aralkyl halogen, such as methyl iodide Or benzyl iodide.Also other reactants with good leaving group, such as alkyl trifluoromethyl sulfonic acid, alkyl methyl sulphur can be used Hydrochlorate and alkyl tosilate.Quaternary amine has the nitrogen of positively charged.Pharmaceutically acceptable counter ion counterionsl gegenions include chlorine, bromine, iodine, Trifluoroacetate and acetate.Ion exchange resin can be used to introduce selected counter ion counterionsl gegenions.

The prodrug of disclosed compound is also considered herein.Prodrug is active or inactive compound, and prodrug is in quilt After being administered to experimenter, acted on by body physiological, such as hydrolysis, metabolism etc. are chemically modified as reactive compound.As herein Used in term " prodrug " refer to pharmaceutically acceptable derivates, such as ester, acid amides and phosphate so that the derivative institute The vivo biodistribution converted product for obtaining is the active medicine as defined in the compound of this paper.Prodrug preferably has good water-soluble Property, the bioavilability of raising and it is easy to metabolism active inhibitors in vivo.The prodrug of compound as herein described can pass through Modified to be present in the functional group in compound to prepare, described modification mode is, by routine operation or in vivo, with parent Compound cracking is opened.It is well known by persons skilled in the art with regard to preparation and using the adaptability and technology of prodrug, containing ester The general discussion of prodrug sees Svensson and Tunek, the and of Drug Metabolism Reviews 165 (1988) Bundgaard,Design of Prodrugs,Elsevier(1985)。

Term " prodrug " also refers to the carrier including any covalent bonding, and when prodrug is applied to experimenter, they are in vivo The active parent drug of the release present invention.Because relative to agents, prodrug often has enhanced property, such as dissolve Degree and bioavilability, the compound of this paper can also be delivered in the form of prodrug.Therefore, the prodrug of the compounds of this invention, pass The method and the composition containing this prodrug for sending prodrug is also worthy of consideration.The prodrug of the compounds of this invention typically by It is prepared by the mode of one or more functional group modifications of compound, in this approach, it is modified be by routine operation or Internal cracking obtains parent compound.Prodrug includes that the compound with phosphonate ester and/or amino group is sent out with any group Give birth to functionalization and crack in vivo, respectively obtain corresponding amino and/or phosphonate groups.The example of prodrug includes but does not limit In the compound with acylated amino group group and/or phosphonate ester or phosphonate ester amide group.In specific example, prodrug is Lower alkyl phosphonate, such as isopropyl phosphonate ester.

The protected derivative of disclosed compound is also considered.Can be used for the various suitable of disclosed compound Blocking group see Greene and Wuts, Protective Groups in Organic Synthesis；3rd Ed.； John Wiley&Sons,New York,1999。

In general, blocking group removal under certain condition does not interfere with the remainder of the molecule.These Method is known in the art, including sour water solution, hydrogenolysis etc..A kind of preferred method includes the removal of ester, such as using Louis This acid condition cracking phosphonate ester, mediates the cracking of ester, to obtain free phosphonic acids ester group such as under the conditions of TMS-Br.Second excellent The method of choosing includes removing blocking group, such as in suitable solvent system, such as alcohol, acetic acid or their mixture are sharp Benzyl is removed with carbon palladium hydrogenolysis.Tert-butoxy group, including Boc protecting group, can be by suitable solvent system In, such as water, dioxanes and/or dichloromethane are removed, such as hydrochloric acid or trifluoroacetic acid using inorganic acid or organic acid.Another Exemplary blocking group is trityl, and it is applied to protection amino and hydroxyl-functional amino.Other Conventional protecting groups It is known, suitable blocking group is that those skilled in the art are selectable, sees Greene and Wuts, Protective Groups in Organic Synthesis；3rd Ed.；John Wiley&Sons,New York,1999.When amine is gone to protect During shield, the salt for obtaining easily can be neutralized to obtain unhindered amina.Similarly, when an acid moieties, such as one phosphonic acid moiety After exposure, the compound can be separated as acid compound or as its salt.

Compound

Disclosed herein is new periphery and limit Cannabined receptor mediation compound, for treating such as fibrillatable, glycosuria Disease, obesity and liver cancer.Cannabined receptor can be CB₁And/or CB₂Acceptor.The compound phase is for CB₂To CB₁It can be base It is nonselective in sheet, or to CB₁Acceptor or CB₂Acceptor is selective.In a preferred embodiment, Cannabined receptor Mediation compound is to CB₁Receptor-selective.

In certain embodiments, Cannabined receptor mediation compound is Cannabined receptor inverse agonist, particularly CB₁ Inverse agonist.In certain embodiments, Cannabined receptor mediation compound is neutral antagonist.CB₁Inverse agonist is One kind is relative to CB₁The medicine that activator itself tells on, and also CB can be prevented₁The effect of activator.In contrast, CB₁Neutral antagonist can only play the effect of the latter and (prevent CB₁The effect of activator), but on oneself without impact.CB₁Instead Prove typically by the reduction GTPgammaS combinations of medicine and/or the ability of increase adenyl cyclase activity to excitement 's.Compound can show the active sense to GTPgammaS or beta-protein inhibitor or GTPgammaS and beta-protein inhibitor Sexual deviation.

In certain embodiments, compound preferably peripheral tissues (for example, adipose tissue, liver, muscle, lung, kidney, Macrophage, pancreatic beta cell and intestines and stomach) in targeting CB₁Acceptor, without in brain tissue with CB₁Acceptor interaction. The effect of periphery mediation is kept, but CNS side effects minimize or are not in.

Evidence suggests, the metabolic effect of Endocannabinoids is, at least part of by CB₁Acceptor is in intermediary of peripheral tissues Lead, and neurological side effects are by CB₁What acceptor was mediated in the brain.This shows the CB with the ability for penetrating brain for reducing₁ Receptor antagonist can cause less psychoneural side effect, if it exists, while member-retaining portion or most of its metabolism Advantage.In order to limit CB₁The metabolism effect of receptor antagonist, this can be acted on more than one by design one kind in cell The double activity compound of target is improved with affecting identical metabolic process.For example, the second target may include but be not limited to, Enzyme induction type nitricoxide synthase (iNOS) or AMP kinases (AMPK), because result of study shows, suppress iNOS or swash AMPK living improves insulin resistance, and reduce fibrillatable and inflammation (Shinozaki S et al., J.Biol.Chem.2012,286(40),34959-34975；Young RJ et al.,Bioorg.Med.Chem Let.2000,10(6),597-600；da Silva Morais A et al.,Clin.Sci.2010,118(6),411- 420).The CB of some embodiments disclosed herein₁Blocking compound has the infiltrative compound of low-down brain, and carries The generation of the high metabolin for directly suppressing iNOS or activation AMPK.

In certain embodiments, it is less than with the ratio of the Cmax in blood plasma according to Cmax in the brain 0.1, can characterize and confirm the cannboid CB that periphery limits₁Receptor-mediated compound, test is directed to after intravenous injection Mouse.It is preferred that periphery limits cannboid CB₁The brain C of receptor-mediated compound_{It is maximum}With plasma C_{It is maximum}Ratio be less than 0.05.Particularly preferably Periphery limits the brain C that Cannabined receptor mediates compound_{It is maximum}With plasma C_{It is maximum}Ratio be less than 0.025.

In one embodiment, compounds as disclosed herein, or its pharmaceutically acceptable salt or ester, with knot Structure：

Q is H, hydroxyl or optionally substituted alkoxyl；

R¹、R²And R³It is each independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, nitre Base, hydroxyl, optionally substituted alkoxyl, amino, amino carbonyl, optionally substituted sulfonyl, optionally substituted aryl, optionally take The heteroaryl in generation, optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono Base, optionally substituted phosphinyl, aralkyl, optionally substituted mercaptan, or R²And R³Optionally substituted cycloalkyl is formed together with Z Ring or optionally substituted heterocycloalkyl ring；

Z is B, N ,-CH- or P；

D is-S (O)₂- or-C (O)-；With

N is 0-5.

In some embodiments of Formula I, R²And R³Optionally substituted cycloalkyl ring or optional is not formed together with Z Substituted heterocycloalkyl ring.In some embodiments of Formula I, R²And R³It is independently of one another that optionally substituted alkyl is (special It is not low alkyl group).In some embodiments of Formula I, R²And R³It is independently of one another alkyl (particularly lower alkyl Base).In some embodiments of Formula I, R²And R³Each identical (particularly low alkyl group).In some realities of Formula I In applying scheme, Z is N and R²And R³Optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring are not formed together with Z. In some embodiments of Formula I, Z is N and R²And R³It is independently of one another alkyl (particularly low alkyl group) or aralkyl. In some embodiments of Formula I, Z is N and R²And R³Each identical (particularly low alkyl group).Formula I some In embodiment, D is-S (O)₂-。

This paper further disclosed compound, or its pharmaceutically acceptable salt or ester, with structure：

Wherein R²⁵It is optionally substituted N- heterocycles.In certain embodiments, R²⁵N- heterocycles may be selected from pyrrole radicals, H- Pyrrole radicals, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazoles base (including 1,2,3 and 1,2,4 oxadiazoles bases), isoxazolyl, Furan a word used for translation base, thiazolyl, isothiazole, pyrazoles, pyrazolinyl, pyrazolidinyl, imidazole radicals, imidazolinyl, triazolyl are (including 1,2,3 With 1,3,4 triazolyls), tetrazole radical, thiadiazolyl group (including 1,2,3 and 1,3,4 thiadiazolyl groups), dithiazole base, pyridine radicals, pyrimidine Base, pyridazinyl, pyrazinyl, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl or triazine radical.

In some embodiments of Formula I or Ia, each X and Y is optionally substituted aryl.

Wherein each R⁴、R¹⁰And R¹¹It is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, nitre Base, hydroxyl, optionally substituted alkoxyl, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl Base, optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono optionally take The phosphinyl in generation；

A is-CH₂-、-O-、-CH(CF₃)-、-CF₂-、-CCl₂- ,-N (alkyl)-,-N (aryl)-, single or double substituted C- Miscellaneous alkyl, single or double substituted C- alkyl, single or double substituted C- aryl, single or double substituted C- cycloalkyl ,-CH (COOR²⁰)-、-CH(CN)-、-S-、-S(O)-、-S(O₂)-or-N (O)-, wherein R²⁰It is H or alkyl；

A and b are individually 0-5；With

C is 0-7.

In further embodiment, compounds as disclosed herein, or its pharmaceutically acceptable salt or ester, have Structure：

Wherein X and Y are each independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkanes Base, optionally substituted Heterocyclylalkyl or optionally substituted alkyl；Q is H, hydroxyl or optionally substituted alkoxyl；With

U is

Wherein R^a- C (=NH) R¹, wherein R¹Be H, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, Nitro, hydroxyl, optionally substituted alkoxyl, amino, amino carbonyl, optionally substituted sulfonyl, optionally substituted aryl, optionally Substituted heteroaryl, optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono Base or optionally substituted phosphinyl；With

R^bIt is a substituted sulphonyl or substituted carbonyl.

Wherein R²And R³It is each independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, nitre Base, hydroxyl, optionally substituted alkoxyl, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl Base, optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono, optionally take The phosphinyl in generation, or R²And R³Optionally substituted cycloalkyl ring, optionally substituted heterocycloalkyl ring are formed together with Z；It is optionally substituted Aromatic ring or optionally substituted hetero-aromatic ring；

Z is B, N ,-CH- or P；With

N is 0-5.

In some embodiments of Formulae II a, R²And R³Optionally substituted cycloalkyl ring is not formed together with Z or is appointed Choose the heterocycloalkyl ring in generation.In some embodiments of Formulae II a, R²And R³It is independently of one another optionally substituted alkane Base (particularly low alkyl group).In some embodiments of Formulae II a, R²And R³It is independently of one another that alkyl is (particularly low Level alkyl).In some embodiments of Formulae II a, R²And R³Each identical (particularly low alkyl group).In Formulae II a Some embodiments in, Z is N and R²And R³Optionally substituted cycloalkyl ring or optionally substituted heterocycle alkane are not formed together with Z Basic ring.In some embodiments of Formulae II a, Z is N and R²And R³It is independently of one another alkyl (particularly low alkyl group) Or aralkyl.In some embodiments of Formulae II a, Z is N and R²And R³Each identical (particularly low alkyl group).

Wherein each R¹²It is independently selected from optionally substituted alkyl, optionally substituted miscellaneous alkyl, hydroxyl, optionally substituted alcoxyl Base or optionally substituted alkyl amino, optionally substituted aryl, halogen, cyano group, nitro, acyl group or carbonyl；With

D is 0-5.

In some embodiments of Formulae II, IIa, IIb or IIc, each X and Y is optionally substituted aryl or appoints Choose the heteroaryl in generation.

Wherein each R¹³、R¹⁴And R¹⁵Be independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, It is nitro, hydroxyl, optionally substituted alkoxyl, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted miscellaneous Aryl, optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono or optional Substituted phosphinyl；

F and g are individually 0-5；With

G is 0 to 7.

In certain embodiments, the compound disclosed herein for existing can be " Ν Η₂" dynamic isomer, or " NH " Dynamic isomer, or combination.For example：

Therefore, there is disclosed herein the following " Ν of Formula I and Formulae II (wherein substituent is as defined above) Η₂" dynamic isomer：

Formula II *, wherein U are

In some embodiments of any of the above described chemical formula, R¹It is optionally substituted alkyl (for example, low alkyl group, sulphur The low alkyl group that alcohol replaces), amino carbonyl (for example, acetylamino), or optionally substituted phenyl (for example, the benzene of halogen substiuted Base, particularly 4 halobenzene bases).

In some embodiments of any of the above described chemical formula, Q is H.

In some embodiments of any of the above described chemical formula, A is-CH₂-、-CF₂-、-O-、-CH(CF₃)-,-N (alkane Base)-, or single or double substituted C- aryl.

The specific example of compound disclosed herein may include one or more asymmetric centers；Therefore these compounds can To exist with different stereoisomer forms.Therefore, the compound and composition of this paper can be used as single pure enantiomer Or provide including racemic mixture as stereoisomer mixture.In certain embodiments, the compound of this paper is to close Into to or be purified to the form of substantially enantiomer-pure, for example 90% enantiomeric excess, 95% enantiomeric excess, 97% Enantiomeric excess, the form of even greater than 99% enantiomeric excess, e.g. enantiomer-pure.

For example, the compound of Formula I can be stereoisomer mixture or cis/trans isomers, rotational isomeric The form of body or dynamic isomer.In certain embodiments, the compound of Formula I can be S enantiomers, such as following institute Show：

In certain embodiments, medicament disclosed herein is mixing cpd, including (i) CB₁Receptor-mediated Frame (for example, inverse agonist or neutral antagonist), and (ii) second treatment support.In certain embodiments, it is disclosed herein Any chemical formula-NH-C (NH) R¹- part or-N=C (NH₂)R¹- part all constitutes the second treat support at least one Point.In certain embodiments, the second treatment support can experience cracking in vivo, and so as to discharge the second treatment support, the support can Retain at least a portion of its therapeutic activity.For example, in the case where melbine is used as the second treatment support, the mixing of gained Compound can have therapeutic efficiency during the internal metabolism of compound, and the effect is due not only to its blocking CB₁Acceptor, also returns Because of the release of in melbine --- a kind of widely used antidiabetic ---.Cracking in vivo can pass through drug metabolism The effect of enzyme, such as Cytochrome P450 isoform any position in vivo occurs, but generally occurs in liver,.At some In embodiment, cracking occurs in-NH-C (NH) R¹Part or-N=C (NH₂)R¹Partly with the carbonamidine of compound (carboximidiamide) on the key between the C atoms of part.

Second treatment support of example includes antidiabetic, anticancer, antiobesity agent and antifibrotic agents.

Second treatment support or as following formula is generally represented, or as in the clear and definite of unsubstituted nitrogen end Additives (attachment).

In certain embodiments, the compound of this paper has the chemical stability for improving so that the half-life of blood plasma exists In the range of 1-16 hours, more preferably in the range of 4-8 hours.

In certain embodiments, disclosed herein dose is mixing cpd, including (i) CB₁Receptor-mediated support (for example, inverse agonist or neutral antagonist), and (ii) diagnosticum or entity.In certain embodiments, it is disclosed herein - NH-C (NH) R of any chemical formula¹- part or-N=C (NH₂)R¹- part all constitutes at least a portion of diagnosticum or entity (for example, antibody, biotin labeling, include¹⁸F or¹¹The group of C).Optionally with PET, SPECT imaging, it is autoradiographic Diagnosis of partial, can by obtaining in X, Y or Q position displaced atom of any chemical formula, with produce with²H、³H、¹¹C、¹³N、¹⁵O、¹⁸F、^75-77Br、^123-131I or^99mRadio isotope atom has the part of high-affinity as Tc.Diagnosis group or reality Body can be used in image pathological diagnosis, such as fibrillatable, cancer, angiocardiopathy, metabolism, inflammatory and neurodegeneration disease Disease.Diagnostic compounds can serve as fluorescence probe, affinity tag, in nuclear medicine, optical imagery, such as PET, SPECT.This A little compounds include a targeting CB for being connected at least one diagnostic signal entity₁Support.One CB comprising diagnosis entity₁ Support can target at least one mark of pathological state, such as protein, enzyme or the cell receptor expressed under pathological state.

In certain embodiments, compounds as disclosed herein has low or does not have Cytochrome P450 active, Even if being also very slight it means that medicament causes the interaction between medicine.

In certain embodiments, compounds as disclosed herein has the CB of 0.1-20nM₁R binding affinities, and CB₁/CB₂Selectively it is at least 20 times, or more preferably 100 times or higher.

Fig. 1 and 2 illustrates the general synthetic method for preparing compounds as disclosed herein.Synthetic schemes I is described from city Sell available suitable substituted 2- phenyl acetophenones and be converted to the new CB with double activity₁Selective inverse agonist compounds General route.Synthetic method is applied to the replacement -4,5- pyrazolines of 1,3,4- tri- of Formula I.For example, using containing 37% first The piperidines and acetic acid of aldehyde, 1- (4- chlorphenyls) -2- Phenyl ethyl ketones can be converted into 1- (4- chlorphenyls) -2- phenyl propyl- 2- alkene -1- Ketone (step a).It is stupid with hydrazine hydrate process acryloyl in the 2- propyl alcohol of backflow, generate 3- (4- chlorphenyls) -4- phenyl -4,5- bis- Hydrogen -1H- pyrazoles (step b) (J.Agric.Food Chem.1979,27,406).Compound is obtained by chloro sulfonyl isocyanate The sulfonylcarbamic acid ester of VI types, then pyrazoline and sulfonylcarbamic acid ester condensation (step c and d), obtain diaryl Pyrazoline acyl sulfonamides compound VII (step e).There is chlorination reaction with phosphorus pentachloride in the chlorobenzene of backflow in the product, Obtain foregoing imine acyl chloride compound VIII (step f) (J.Med Che.2004,47,627, and Che, Ber.1966,99,2885,Bioorg Med.Chem.Lett,2010,20,1752).Imido acyl chloride and B amidine hydrochloric acid salt etc Compound in the presence of triethyl amine in the mixture of methyl alcohol and dichloromethane occur coupled reaction (step g), with produce The compound IX of the hydrogen-based -1H- pyrazoles -1- formamidine compounds of 4,5- bis- etc.This compound can prepared using chiral column R and S optics pure enantiomers are obtained under the conditions of property HPLC.Alternatively, racemic diaryl pyrazole oxazoline acyl sulfonamides can be in hand Property chromatographic column on separate, to obtain optically pure enantiomer acyl sulfonamides, the material can individually undergo such as step f and g institutes The operation shown.

Synthetic schemes I describes from commercially available available aldehyde and hydrazine to be converted to the new CB with double activity₁It is selective reverse The general route of agonist compound.The synthetic method is applied to the replacement 4,5- pyrazolines of 1,3,5- tri- of Formulae II.Close Bioorg Med.Chem.Lett, 2010,20,1752and/or J.Med Che.2007,50,5951 are may be referred to into method It is adjusted.With acetone acid treatment aldehyde, such as benzaldehyde here as described in step a, is then processed in absolute ethyl alcohol with chloroacetic chloride (step b) obtains α, beta unsaturated ketone ester compound XI.Ethanol and acetic acid (flow back in the solution of step c) 4- chlorophenyl hydrazines and Compounds X I, obtains pyrazoline ester compounds XII.Ester is hydrolyzed in ethanol KOH solution, the precursor acid compound for coupling is obtained XIII (step d).The acid can in the basic conditions using suitable substituted phenyl sulfonyl amine, (step e) suitably replaces ammonia (step f) is coupled base sulfonamide, respectively obtains the acyl sulfonamides of compounds X IV types and compounds X V-type.In the presence of base By with POCl₃Process or use PCl in the chlorobenzene of backflow₅Process, these compounds each can individually be changed into imines acyl Chlorine (compounds X VI and XVII) (step g).In the presence of base, by sending out with the compound of ethanamidine or SMethyl thiocarbamides etc Raw reaction, can obtain final racemic compound (XVIII and XIX), and they can be separated by chirality HPLC, be obtained To the final compound of enantiomer-pure.

Composition and using method

The Cannabined receptor mediation agent that periphery disclosed herein limits is unique, and they can improve metabolic syndrome All or at least one aspect.They reduce food intake and body weight, reverse insulin and leptin resistance, invert fatty liver (fat Fat liver), and they can be used to treat obesity, diabetes (for example, diabetes B), and non-alcoholic to improve dyslipidemia With alcoholic fatty liver disease (NAFLD/AFLD), the latter is hazards for insulin resistance, cirrhosis and liver cancer, Yi Yin Play dyslipidemia, nephrosis, gout and the fibrillatable of artery sclerosis heart disease.Medicament disclosed herein can be kept away Exempt to cause the side effect in terms of spirit, to avoid the CB using global effect₁Antagonist.

Diabetic disorders can be type 1 diabetes, diabetes B, Glucose tolerance test is not enough, and/or insulin resistance.

There is disclosed herein the method for treating obesity symbiosis disease.The symbiosis disease can selected from diabetes, Metabolic syndrome, dementia and heart disease.In further embodiment, the symbiosis disease is selected from hypertension；Gall-bladder disease Disease；Gastrointestinal dysfunction；Menoxenia；Degenerative arthritis；Venous stasis ulcer；Pulmonary ventilation deficiency syndrome；Sleep-respiratory Suspend；Snoring；Coronary artery disease；Disease；Pseudotumor cerebri；Accident proneness；The operation risk of increase；Bone joint It is scorching；High cholesterol；And liver, ovary, uterine neck, uterus, breast, prostate, the incidence of disease of the malignant tumour of gall-bladder for increasing.

There is disclosed herein the method for the adipose tissue deposition of prevention or reverse experimenter.By preventing or reversing fatty group Knit deposition, it is contemplated that compound disclosed herein can reduce the incidence of disease or the order of severity of obesity, so as to reduce the incidence of disease Or the order of severity of related symbiosis disease.

Other side disclosed herein includes a kind of pharmaceutical composition for applying to experimenter, the pharmaceutical composition Including one or more compound disclosed herein of therapeutically effective amount.The therapeutically effective amount of compound disclosed herein is depended on The physical characteristics of route of administration, the species of treated experimenter and treated experimenter.It is contemplated that specific factor include The order of severity of disease and stage, body weight, diet and shared medicine.Affect the therapeutically effective amount of compound disclosed herein Relation between these factors is that those skilled in the art understands.

In addition to selected molecule, being administered to the pharmaceutical composition of experimenter can include at least one other pharmacy Upper acceptable additive, such as carrier, thickener, diluent, buffer, preservative, surfactant etc..Pharmaceutical composition One or more extra active component, such as antimicrobial, antiinflammatory, anesthetic etc. can also be included.For these systems The pharmaceutically acceptable carrier of agent is conventional.Remington’s Pharmaceutical Sciences,by E.W.Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995), describe to be applied to medicine The composition and preparation of the form delivering compounds as disclosed herein of thing.

In general, the property of carrier depends on the concrete mode of administration for being adopted.For example, parenteral administration is usual Comprising injectable fluid, it is included pharmaceutically with physiologically acceptable fluid as medium, such as water, physiological saline, balance Salting liquid, G/W, glycerine etc..It is conventional for solid composite (for example, the form of pulvis, pill, tablet or capsule) Non-toxic solid carrier can include mannitol, lactose, starch or the magnesium stearate of such as pharmaceutical grade.Except bio-neutral is carried Body, the pharmaceutical composition applied can contain a small amount of non-toxic auxiliary substances, and such as wetting agent or emulsifying agent, preservative and pH is slow Electuary etc., such as sodium acetate or sorbitan monolaurate.

Pharmaceutical composition disclosed herein include by compounds as disclosed herein pharmaceutically acceptable salt and/or The material that solvate is formed.Pharmaceutically acceptable salt is included derived from pharmaceutically acceptable inorganic or organic alkali and acid Material.Specifically disclosed compound has at least one basic group that Acid-Base salt can be formed with acid.The example of basic group Including but not limited to, amino and imino group.Can with the example of the inorganic acid of such basic group forming salt include but It is not limited to, inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.Basic group can also be with following sour forming salt：Organic carboxyl acid, The sulfamic acid that sulfonic acid (sulfonic acid), sulfonic acid (sulfo acid) or phosphoric acid or N- replace, such as acetic acid, propionic acid, ethanol Acid, butanedioic acid, maleic acid, carboxylic acid, citraconic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucosaccharic acid, glucose Aldehydic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-ASA, 2- phenoxy benzoic acids, 2- acetyl oxygen Yl benzoic acid, embonic acid (embonic acid), nicotinic acid or isonicotinic acid, and also amino acid, such as alpha-amido Acid, and also methanesulfonic acid, ethyl sulfonic acid, 2- hydroxymethane sulfonic acids, ethane -1,2- disulfonic acid, benzenedisulfonic acid, 4- toluene sulfonic acides, Naphthalene-2-sulfonic acid, 2- or 3-phoshoglyceric acid, G-6-P or N- cyclohexylsulfamics (form cyclohexylsulfamic Salt (cyclamate)), or other acidic organic compounds, such as ascorbic acid.Particularly, in various acid known to drug world In, suitable salt is included by alkali metal such as potassium and sodium, the salt of alkaline-earth metal such as calcium and magnesium derivative.

Some compounds include can be with least one acidic-group that acid-alkali salt can be formed with inorganic or organic alkali.By nothing The example of the salt that machine alkali is formed includes that presently disclosed compound and alkali metal such as potassium and sodium, alkaline-earth metal such as calcium and magnesium etc. are formed Salt.Similarly, (term " amine " here is understood to include their conjugation for acid compound and organic base, such as amine Acid, unless context clearly illustrates to use unhindered amina) formed salt be also it is considered, including with basic amino acid, aliphatic series Amine, heterocyclic amine, aromatic amine, pyridine, guanidine and amidine.In aliphatic amine, acyclic aliphatic race amine, and ring-type and acyclic double-and three- Alkylamine is particularly suitable for being used in compounds as disclosed herein.In addition it is also possible to using quaternary ammonium counterion.

The specific example of the suitable amine base (and its corresponding ammonium ion) being suitable for use in compounds as disclosed herein Include, but not limited to pyridine, N, N- dimethyl aminopyridines, diazabicyclo nonane, diazabicyclo endecatylene, N- first Base-N- ethamine, diethylamine, triethylamine, diisopropyl list-, double-or three-(2- ethoxys) amine, 2- hydroxyls-tert- butylamine, three (hydroxyls Methyl) methylamine, N, N- dimethyl-N -s (2- ethoxys) amine, three-(2- ethoxys) amine and N- methyl-D-glucosamines." pharmaceutically Other examples of acceptable salt " are shown in Berge et al., J.Pharm.Sci.66:1(1977).

Compounds as disclosed herein can be crystallization, it is possible to be single crystal form, or the polycrystalline of different crystal The composition of type thing.As such, it is possible to provide compound, such as different crystal form, crystallization, liquid with one or more physical form Brilliant or amorphous (unbodied) form.The compound of different physical forms can for example by using different solvent or not Same solvent mixture is recrystallized to prepare.In addition, different polymorphs can for example by entering at different temperatures Row recrystallizes and/or changes in recrystallization process cooldown rate to prepare.The presence of polymorph can be by X-ray come really Recognize, or in some cases by another spectral technique, such as solid phase NMR spectroscopy, IR spectrum or differential scanning calorimetry is confirming.

Pharmaceutical composition can be administered to experimenter, including oral, rectum, intranasal, lung by various mucosal administration patterns Interior or transdermal delivery, or by local delivery to other surfaces.Optionally, said composition can be applied by non-mucosal route, bag Include intramuscular, subcutaneous, intravenous, intra-arterial, in joint, in intraperitoneal, intrathecal, the ventricles of the brain or parenteral route.In other embodiment party In case, the compound can in vitro be applied by being directly exposed to cell, tissue or the organ of experimenter.

For compounding pharmaceutical composition, the compound can be with various pharmaceutically acceptable additives and alkali or medium Combination, to realize the dispersion of compound.Desired additive includes, but are not limited to, pH controlling agents, such as arginine, NaOH, Glycine, hydrochloric acid, citric acid etc..In addition, local anesthetic (for example, benzylalcohol), isotonic agent (for example, sodium chloride, mannitol, D-sorbite), adsorption inhibitor (for example, Tween 80 or Miglyol 812), dissolution enhancers (for example, cyclodextrin and its derivative Thing), in stabilizer (for example, seralbumin) and reducing agent (for example, glutathione) also be included in.Can wrap in the composition Include adjuvant, such as aluminium hydroxide (such as Amphogel, Wyeth Laboratories, Madison, NJ), Freund's adjuvant, MPL^TM (3D-MPL；Corixa, Hamilton, IN) and IL-12 (Genetics Institute, Cambridge, MA), and many suitable other adjuvants known in the art.When composition is liquid, with 0.9% (w/ The tension force of normal saline solution v) measures the tension force of preparation as unit, and is typically applying the tension adjustment to Position will not induce the value of substantial irreversible tissue damage.Generally, the tension force of solution is adjusted to about 0.3-'s about 3.0 Value, e.g., from about 0.5- about 2.0, or about 0.8- about 1.7.

The compound can disperse in alkali or medium, and the alkali or medium may include to have the ability to disperse the compound Hydrophilic compounds, also including any required additive.Alkali can be selected from extensive suitable compound range, including but not It is limited to, the salt of polycarboxylic acids or the polycarboxylic acids, carboxylic acid anhydrides (such as maleic anhydride) and other monomer (for example, (methyl) acrylic acid first Ester, acryllic acid etc.) copolymer, hydrophilic vinyl polymer, such as polyvinyl acetate, polyvinyl alcohol, polyethylene pyrrole Pyrrolidone, cellulose derivative, such as hydroxymethyl cellulose, hydroxypropyl cellulose, and natural polymer, such as deacetylated shell is more Sugar, collagen, mosanom, gelatin, hyaluronic acid, their nontoxic metal salts.Under normal circumstances, biodegradable polymerization Thing is selected as alkali or medium, for example, PLA, poly- (lactic acid-ethanol) copolymer, poly butyric, poly- (hydroxyl fourth Acid-glycolic) copolymer and their mixture.Either-or or in addition, the such as fatty acid ester of synthesis, polyglycereol Fatty acid ester, sucrose fatty ester etc. can serve as medium.Hydrophilic polymer and other mediums can be used alone or It is applied in combination, and the structural intergrity of medium can be strengthened by partially crystallizable, ionic bonding, crosslinking etc..Medium can be with It is various forms, including liquid or viscosity solution, gel, paste, powder, microballoon and film, and be used directly on mucomembranous surface.

The compound can be combined by various methods with alkali or medium, and be closed by diffusion, medium disintegration, formation The aquaporin of connection is discharging compound.In some cases, compound is dispersed in the microcapsules prepared by suitable polymer In (microballoon) or Nano capsule (nanosphere), for example isobutyl group 2- cyanoacrylates (for example see Michael et al., J.Pharmacy Pharmacol.43:1-5,1991), and is dispersed in biocompatible decentralized medium, and this can produce and continue Delivering and the biologically active of longer time.

Compositions disclosed herein can alternatively contain the pharmaceutically acceptable medium needed for close physiological condition, Such as pH adjusting agent and buffer, tension regulator, wetting agent, such as sodium acetate, sodium lactate, sodium chloride, potassium chloride, chlorination Calcium, sorbitan monolaurate and triethanolamine oleate.For solid composite, it is possible to use conventional is pharmaceutically acceptable Nontoxic medium, including for example, the mannitol of pharmaceutical grade, lactose, starch, magnesium stearate, saccharin sodium, talcum, cellulose, Portugal Grape sugar, sucrose, magnesium carbonate etc..

Pharmaceutical composition for applying compound can also be configured to solution, microemulsion or be suitable for high concentration activity into Other ordered structures divided.Medium can be solvent or decentralized medium, the solvent or decentralized medium contain for example water, ethanol, Polyalcohol (such as glycerine, propane diols, liquid macrogol) and its suitable mixture.Can be by using coating such as ovum Phosphatide, desired granular size is maintained in the case where preparation is dispersibled, and the suitable of solution is maintained using surfactant When mobility.In many cases, it is desired to situation is composition includes isotonic agent, and such as sugar, polyalcohol, such as mannitol and mountain Pears sugar alcohol, or sodium chloride.Compound can be realized such as Monostearate and gelatin in the composition comprising absorbent is postponed Extend and absorb.

In certain embodiments, compound is applied in the form of time delivery formulations, and such as composition includes that sustained release is poly- Compound.Said composition can use the medium for protecting against quick release to prepare, such as controlled release vehicles thing, such as polymer, microcapsules Delivery system or bioadhesive gel.In various compositions disclosed herein, in order to extend delivering, can be in the composition Including delay absorbent, such as aluminum monostearate hydrogel and gelatin.When expecting to obtain controlled release preparation, it is adaptable to the present invention's Controlled release binders include any biocompatible controlled release materials, and these materials are inert for activating agent, and can With binding compounds and/or other bioactivators.Many such materials are well known in the present art.Useful controlled release glues Mixture be under the physiological condition of delivery process (for example, in mucomembranous surface or in the presence of body fluid) slow metabolic material Material.Suitable adhesive includes, but not limited to the bioavailable polymer for extended release preparation known in the art and is total to Polymers.Such biocompatible compounds are nontoxic, and are inert to surrounding tissue, will not also cause significant bad Side effect, such as nose stimulation, immune response, inflammation.They are metabolised to while bio-compatible be also easily to remove from vivo Metabolite.

Exemplary polymer for the present invention includes, but not limited to by the copolyester with hydrolyzable ester bond With polymer substrate derived from homopolymerization polyester.These materials of many known in the art are biodegradable, and are produced nontoxic Or the catabolite of low toxicity.Exemplary polymer includes polyglycolic acid and PLA, poly- (DL-LACTIC ACID -co- glycolic), poly- (D-ALPHA-Hydroxypropionic acid -co- glycolic) and poly- (Pfansteihl -co- glycolic).Other useful biodegradable or biological erodable Polymer includes, but not limited to polymer for example poly- (6-caprolactone), poly- (6-caprolactone-CO- lactic acid), poly- (6-caprolactone-CO- Glycolic), poly- (beta-hydroxy-butanoic acid), poly- (alkyl -2- cyanoacrylates), hydrogel, such as poly- (hydroxyethyl methacrylate), Polyamide, poly- (amino acid) (such as L-Leu, glutamic acid, L-Aspartic acid), poly- (ester urea), poly- (2- ethoxy DL- asparagus ferns Acid amides), polyacetal polymer, poe, Merlon, poly- maleic amide, polysaccharide and their copolymer.For preparing Many methods of this preparation be it is well known by persons skilled in the art (see for example, Sustained and Controlled Release Drug Delivery Systems,J.R.Robinson,ed.,Marcel Dekker,Inc.,New York, 1978).Other useful preparations include released microcapsule (U.S. Patent number 4,652,441 and 4,9178,93), in microcapsules and Useful lactic acid-ethanol copolymer in other preparations (U.S. Patent number 4,677,191 and 4,728,721), and for water The sustained-release composition (U.S. Patent number 4,675,189) of dissolubility peptide.

Pharmaceutical composition disclosed herein is aseptic and stable generally under manufacture, storage and use condition.It is aseptic Solution can be prepared by the way that the desired amount of compound is added in a kind of suitable solvent, and the solvent can have cited herein A kind of composition, or the combination of several compositions, depending on demand, then filtration sterilization.Usually, dispersion can be by the way that this be changed Compound and/or other bioactivators are added to containing basic dispersion medium and required other compositions (from those enumerated) Prepare in sterile carrier.In the case of aseptic powdery, preparation method includes vacuum drying and freeze-drying, then by gained The compound powder for arriving is plus any other required compositions, the solution that these other compositions are sterile filtered in advance from it.For The activity of pre- preventing microorganism, can be realized, for example parabens, neoprene by various antiseptics and antifungal agent Alcohol, phenol, sorbic acid, thimerosal etc..

For various treatment methods disclosed herein, can be according to the mode consistent with conventional treatment method by compound Experimenter is delivered to, while the illness to needing treatment or prevent is managed.According to disclosure herein, be enough to prevent Only, under conditions of suppressing and/or improving selected disease or illness or one or more its symptom, prevention or therapeutically effective amount Compound and/or other bioactivators are administered to experimenter in need for the treatment of for a period of time.

The administration of compound disclosed herein can be preventative or curative.If preventative, any Symptom is provided with compound before occurring.The preventative administration of compound can prevent or improve any follow-up lysis. If curative, in symptom (or soon afterwards) for disease or infection occur compound is provided with.

For preventative and curative purpose, the compound is applied to experimenter can be oral or one pass Send, continuous delivering in a long time (for example, continuous percutaneous, mucous membrane or intravenous delivery), or the administration program (example for repeating Such as, repetitive administration program per hour, daily or weekly).The treatment effective dose of compound can be in long-term prevention or Repeated doses in therapeutic scheme, the dosage can produce significant clinical effectiveness, mitigate one or more symptom, or and target The related detectable illness of disease, or illness as described herein.The determination of effective dose in context is normally based on animal Scale-model investigation and subsequent to people's clinical testing, and it also requires with reference to the targeting disease symptom or illness that substantially reduce experimenter Generation or the order of severity administration program guidance.Appropriate model in this respect include for example mouse, rat, bird, dog, Sheep, pig, cat, non-human primates and other acceptable animal models known in the art.Optionally it is determined that effective dose can be with Using external model.During using such model, it is only necessary to by the appropriate concentration of common calculating and adjustment determination and dosage, To apply the compound (for example, can effectively mitigate the dosage of one or more symptom of targeting disease) of therapeutically effective amount. In optional embodiment, for treatment or the purpose for diagnosing, the compound of effective dose or effective dose can easily suppress or Strengthen the selected biologically active of one or more related to disease or illness, it is as described herein.

The actual dose of compound changes according to various factors, and such as the disease indication and particular state of experimenter be (for example, Age, size, health status, symptom degree, predisposing factor of experimenter etc.), time of application and approach, be administered simultaneously other Medicine or treatment, and for causing the concrete pharmacology of compound for expecting activity or biological respinse on experimenter.Can adjust Whole dosage is providing optimal prevention or treatment response.Therapeutically effective amount also implies that, the compound and/or other are biological The treatment beneficial effect of activating agent exceedes its any toxicity or harmful side effect clinically.In method disclosed herein and system The non-limiting therapeutically effective amount scope of compound and/or other bioactivators in agent is about 0.01mg/kg body weight-about 20mg/kg body weight, e.g., from about 0.05mg/kg- about 5mg/kg body weight, or about 0.2mg/kg- about 2mg/kg body weight.

Attending doctor can change dosage, so as to maintain desired concentration (for example, lung or systemic circulation) in target site. Higher or lower concentration can be selected according to delivering mode, delivering mode for example Jing epidermises, rectum, oral cavity, lung, in bone or Intranasal delivery and intravenously or subcutaneously or intramuscular delivering.Also dependent on the release rate modifier amount of the preparation applied, for example, Intrapulmonary is sprayed and powder, oral sustained release and injection particulate or transdermal delivery preparation etc..

Compound disclosed herein can also be with other therapeutic agent common use.Such therapeutic agent includes, but does not limit In antidiabetic, cholesterol-lowering agent, antiinflammatory, antimicrobial, NMPI, LOX suppress It is agent, cytokine antagonist, immunodepressant, anticancer, antivirotic, cell factor, growth factor, immunomodulator, front Row parathyrine or anti-angiogenic antihyperproliferative compound.

Present invention additionally comprises kit, packaging and many container units, its contain pharmaceutical composition as herein described, activity into Point and/or for applying the device of above-mentioned substance, so that disease and other illnesss are prevented and treated in mammalian subject.This Invention additionally provides diagnostic kit.In one embodiment, kit includes container or preparation, the container or system Agent contains one or more compound as herein described.In an example, the composition is formulated in for being delivered to experimenter Pharmaceutical preparation in.The compound is optionally comprised in distribution container in bulk, or the form of unit or multiple-units dosage In.Optional distributor, such as lung or Intranasal sprays coating can be provided.Packaging material optionally include label or explanation, these Label or explanation are used to refer to these packaging medicaments to be used for any therapeutic purposes and/or how to use.

Embodiment

Example embodiment 1：

PCl is added in the 3mL chlorobenzenes (synthetic route 1) containing solsonylurea compounds 3 (446mg, 1.00mmol)₅, so After heat the mixture 1 hour.Then evaporation solvent, imine acyl chloride residue is dissolved in dichloromethane, and uses ethanamidine salt Hydrochlorate (3.06mmol) is in methyl alcohol:Dichloromethane:Et3N(2:1:1) dropwise dropwise addition is processed the premix at 78 DEG C, and And it is warming up to ambient temperature overnight.Reactant mixture is extracted in dichloromethane, is washed with water, using hexane:Ethyl acetate (6:4) By purified by flash chromatography, above-mentioned amidine compound A, yield 30-40% are obtained.Performance data is shown in table 1.

Synthetic route 1

Or ' NH₂' dynamic isomer

Bibliography：Biog.Med.Chem.Lett 2009,19,5675-5678

Example embodiment 2

EDCI (2eq) is added in the dichloromethane (synthetic schemes 2) containing acid compound XIII (1.2mg, 4mmol), DMAP (2eq) and 2- naphthalene sulfonylamides (1.1eq), ans is stirred overnight.Then it is acidified the mixture with 1N HCl, and with water and two Chloromethanes is extracted.Evaporation dichloromethane layer, thick residue is ground with IPA, obtains pure solsonylurea compounds 4, and yield is 40- 50, depending on regenerant.Then compound 4 is dissolved in into dichloromethane and PCl₅, and the mixture is heated at reflux into 24 hours. Imido acyl chloride residue is further dissolved in dichloromethane, and with methyl isothiourea hydriodate (methyl Carbamimidothioate hydroiodide) (2mmol) in methyl alcohol：Dichloromethane:Et₃N(2:1:1) premix in Dropwise dropwise addition is processed at 78 DEG C, and is warming up to ambient temperature overnight.Reactant mixture is extracted in dichloromethane, is washed with water Wash, using hexane:Ethyl acetate (6:4) by purified by flash chromatography, above-mentioned amidine compound B, yield 50-60% are obtained.It is special Property data are shown in table 4.

Synthetic route 2

Bibliography：1.Biorg.Med.Chem.Lett2010,120,1752,1757.

2.J.Med.Chem.2007,50,5951-5966.

Compound disclosed herein using mouse brain cell membrane and³H-CP55540 matches somebody with somebody as the radioactivity of tagged ligand In body substitutability analysis, there is high-affinity to mouse CB1 acceptors.For example, compound MRI-1950 has the K of 1.2nM_iCB1.This Outward, compound disclosed herein can be low lipophilic.For example, the MRI-1950 of compound has 3.3 CLogP values, this So that it has low lipophilicity, therefore improve its water solubility.

Table 1

Table 2

Table 3

Table 4

In following numbering items, multiple embodiments are described：

1. a kind of compound, or its pharmaceutically acceptable salt or ester, with structure：

Q is H, hydroxyl or optionally substituted alkoxyl；

Z is B, N ,-CH- or P；

D is-S (O)₂- or-C (O)-；With

N is 0-5.

2. such as the compound of item 1, wherein R²And R³Optionally substituted cycloalkyl ring or optionally substituted is not formed together with Z Heterocycloalkyl ring.

3. such as the compound of item 2, wherein R²And R³It is independently of one another optionally substituted alkyl.

4. such as the compound of item 3, wherein R²And R³Each identical and respectively low alkyl group, and Z is N.

5., such as the compound of item 1, wherein compound has following structures：

Wherein R²⁵It is optionally substituted N- heterocycles.

6., such as the compound of item any one of 1-5, wherein each X and Y is optionally substituted aryl.

7., such as the compound of item 5, the wherein compound has following structures：

A and b are individually 0-5；With

C is 0-7.

8., such as the compound of item 7, the wherein compound has following structures：

9., such as the compound of item 8, the wherein compound has following structures：

10., such as the compound of item 7, the wherein compound has following structures：

The compound of 11. such as items 10, the wherein compound has following structures：

A kind of 12. compounds, or its pharmaceutically acceptable salt or ester, with following structures：

U is

Wherein R^a- C (=NH) R¹, wherein R¹Be H, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, Nitro, hydroxyl, optionally substituted alkoxyl, amino, amino carbonyl, optionally substituted sulfonyl, optionally substituted aryl, optionally Substituted heteroaryl, optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono Base or optionally substituted phosphinyl；And R^bIt is a substituted sulphonyl or substituted carbonyl.

The compound of 13. such as items 12, the wherein compound has following structures：

Z is B, N ,-CH- or P；With

N is 0-5.

14. as item 13 compound, wherein R²And R³Optionally substituted cycloalkyl ring, optionally substituted is not formed together with Z Heterocycloalkyl ring；Optionally substituted aromatic ring or optionally substituted hetero-aromatic ring.

15. as item 13 compound, R²And R³It is independently of one another optionally substituted alkyl (particularly low alkyl group).

16. as item 15 compound, wherein R²And R³Each identical and respectively low alkyl group, and Z is N.

The compound of 17. such as items 13, the wherein compound has following structures：

Wherein each R is independently selected from optionally substituted alkyl, optionally substituted miscellaneous alkyl, hydroxyl, optionally substituted alcoxyl Base or optionally substituted alkyl amino, optionally substituted aryl, halogen, cyano group, nitro, acyl group or carbonyl；With

D is 0-5.

The compound of 18. such as items 13, the wherein compound has having structure：

Wherein R²⁵It is optionally substituted N- heterocycles.

The compound of 19. such as items 18, the wherein compound has having structure：

F and g are individually 0-5；With

G is 0 to 7.

The compound of 20. such as items 19, the wherein compound has having structure：

The compound of 21. such as items 20, the wherein compound has having structure：

The compound of 22. such as items 19, the wherein compound has having structure：

The compound of 23. such as items 22, the wherein compound has having structure：

24. as item any one of 1-23 compound, wherein R¹It is that (for example, low alkyl group, mercaptan take optionally substituted alkyl The low alkyl group in generation), amino carbonyl (for example, acetylamino) or optionally substituted phenyl (phenyl that for example, halogen replaces).

25. as item any one of 1-24 compound, wherein Q is H.

26. as item any one of 1-25 compound, wherein A is-CH₂-、-CF₂- ,-O- or-CH (CF₃)-。

A kind of 27. pharmaceutical compositions, including the compound of item any one of 1-26, and it is at least one pharmaceutically acceptable Additive.

A kind of 28. pharmaceutical compositions, including the compound of the item any one of 1-26 of the therapeutic dose of unit dosage form, and At least one pharmaceutically acceptable additive.

29. it is a kind of for experimenter for treat obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, Obesity symbiosis disease, cause the method that is susceptible to suffer from dyslipidemia, nephrosis or the gout of arteriosclerotic heart disease, Including the compound of the item any one of 1-26 that therapeutically effective amount is applied to subject in need.

The method of 30. such as items 29, including for subject's obesity.

The method of 31. such as items 29, including for subject's diabetes.

A kind of 32. methods of the prevention or reverse adipose tissue deposition for experimenter, including tested to have this to need Person applies the compound of the item any one of 1-26 of effective dose.

The method of 33. such as item any one of 29-32, it is smart that administrations of the wherein compound does not substantially produce unfavorable nerve The impact of refreshing disease.

The method of 34. such as item any one of 29-34, the administration of the wherein compound causes in brain in Cmax and blood plasma most The ratio of big concentration is less than 0.1.

The principle of compound disclosed by the invention, composition and method can be used in the possibility embodiment of many, therefore It should be understood that exemplary embodiment is the preferred example of the present invention, and it is not construed as the limit to the scope of the invention System.

Claims

Wherein X and Y be each independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, appoint Choose the Heterocyclylalkyl or optionally substituted alkyl in generation；

Q is H, hydroxyl or optionally substituted alkoxyl；

R¹, R²And R³It is each independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, nitro, hydroxyl It is base, optionally substituted alkoxyl, amino, amino carbonyl, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted Heteroaryl, optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono, appoint Choose phosphinyl, aralkyl, the optionally substituted mercaptan in generation, or R²And R³Optionally substituted cycloalkyl ring is formed together with Z or is appointed Choose the heterocycloalkyl ring in generation；

Z is B, N ,-CH- or P；

D is-S (O)₂- or-C (O)-；With

N is 0-5.

2. the compound of claim 1, wherein R²And R³Optionally substituted cycloalkyl ring or optionally substituted is not formed together with Z Heterocycloalkyl ring.

3. the compound of claim 2, wherein R²And R³It is independently of one another optionally substituted alkyl.

4. the compound of claim 3, wherein R²And R³Each identical and respectively low alkyl group, and Z is N.

5. the compound of claim 1, wherein compound has following structures：

Wherein R²⁵It is optionally substituted N- heterocycles.

6. the arbitrary compound of claim 1-5, wherein each X and Y is optionally substituted aryl.

7. the compound of claim 5, wherein compound has following structures：

Wherein each R⁴、R¹⁰And R¹¹Be independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, nitro, Hydroxyl, optionally substituted alkoxyl, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, Optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono or optionally substituted Phosphinyl；

A is-CH₂-、-O-、-CH(CF₃)-、-CF₂-、-CCl₂- ,-N (alkyl)-,-N (aryl)-, the miscellaneous alkane of single or double substituted C- Base, single or double substituted C- alkyl, single or double substituted C- aryl, single or double substituted C- cycloalkyl ,-CH (COOR²⁰)-、-CH (CN)-、-S-、-S(O)-、-S(O₂)-or-N (O)-, wherein R²⁰It is H or alkyl；

A and b are individually 0-5；With

C is 0-7.

8. the compound of claim 7, wherein compound has following structures：

9. the compound of claim 8, wherein compound has following structures：

10. the compound of claim 7, wherein compound has following structures：

The compound of 11. claims 10, the wherein compound have following structures：

Wherein X and Y be each independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, appoint Choose the Heterocyclylalkyl or optionally substituted alkyl in generation；Q is H, hydroxyl or optionally substituted alkoxyl；With

U isOr

Wherein R^a- C (=NH) R¹, wherein R¹Be H, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, nitro, It is hydroxyl, optionally substituted alkoxyl, amino, amino carbonyl, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted Heteroaryl, optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono or Optionally substituted phosphinyl；With

R^bIt is a substituted sulphonyl or substituted carbonyl.

The compound of 13. claims 12, the wherein compound have following structures：

Wherein R²And R³Be each independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, nitro, Hydroxyl, optionally substituted alkoxyl, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, It is optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono, optionally substituted Phosphinyl, or R²And R³Optionally substituted cycloalkyl ring, optionally substituted heterocycloalkyl ring are formed together with Z；Optionally substituted virtue Ring or optionally substituted hetero-aromatic ring；

Z is B, N ,-CH- or P；With

N is 0-5.

The compound of 14. claims 13, wherein R²And R³Optionally substituted cycloalkyl ring, optionally substituted is not formed together with Z Heterocycloalkyl ring；Optionally substituted aromatic ring or optionally substituted hetero-aromatic ring.

The compound of 15. claims 13, R²And R³It is independently of one another optionally substituted alkyl (particularly low alkyl group).

The compound of 16. claims 15, wherein R²And R³Each identical and respectively low alkyl group, and Z is N.

The compound of 17. claims 13, the wherein compound have following structures：

Wherein each R¹²Be independently selected from optionally substituted alkyl, optionally substituted miscellaneous alkyl, hydroxyl, optionally substituted alkoxyl or Optionally substituted alkyl amino, optionally substituted aryl, halogen, cyano group, nitro, acyl group or carbonyl；With

D is 0-5.

The compound of 18. claims 13, the wherein compound have having structure：

Wherein R²⁵It is optionally substituted N- heterocycles.

The compound of 19. claims 18, the wherein compound have having structure：

Wherein each R¹³、R¹⁴And R¹⁵Be independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano group, nitro, Hydroxyl, optionally substituted alkoxyl, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, Optionally substituted carboxyl, acyl group, optionally substituted thiazolinyl, optionally substituted alkynyl, optionally substituted phosphono or optionally substituted Phosphinyl；

F and g are individually 0-5；With

G is 0 to 7.

The compound of 20. claims 19, the wherein compound have having structure：

The compound of 21. claims 20, the wherein compound have having structure：

The compound of 22. claims 19, the wherein compound have having structure：

The compound of 23. claims 22, the wherein compound have having structure：

The compound of 24. any one of claim 1-23, wherein R¹It is that (for example, low alkyl group, mercaptan take optionally substituted alkyl The low alkyl group in generation), amino carbonyl (for example, acetylamino), or optionally substituted phenyl (phenyl that for example, halogen replaces).

The compound of 25. any one of claim 1-24, wherein Q is H.

The compound of 26. any one of claim 1-25, wherein A is-CH₂-、-CF₂- ,-O- or-CH (CF₃)-。

The compound of 27. claims 1, wherein D are-S (O)₂-。

The compound of 28. claim 1 or claim 27, wherein n is 0.

The compound of 29. claims 1,27 or 28 any one, wherein X and Y is individually optionally substituted phenyl, and Q is H.

The compound of 30. any one of claim 1-29, wherein-NH-C (NH) R¹- part or-N=C (NH₂)R¹- partly include Therapeutic support, the support is selected from antidiabetic, anticancer, antiobesity agent and antifibrotic agents.

The compound of 31. any one of claim 1-29, wherein-NH-C (NH) R¹- part or-N=C (NH₂)R¹- partly include Diagnosticum.

A kind of 32. pharmaceutical compositions, including the compound of any one of claim 1-31, and it is at least one pharmaceutically acceptable Additive.

A kind of 33. pharmaceutical compositions, including the compound of any one of claim 1-31 of the therapeutic dose of unit dosage form, with And at least one pharmaceutically acceptable additive.

34. it is a kind of for experimenter for treating obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, obesity Disease symbiosis disease, cause the method that is susceptible to suffer from dyslipidemia, nephrosis or the gout of arteriosclerotic heart disease, including The compound of any one of claim 1-31 of therapeutically effective amount is applied to subject in need.

The method of 35. claims 34, including for subject's obesity.

The method of 36. claims 34, including for subject's diabetes.

A kind of 37. preventions for experimenter or the methods for reversing adipose tissue deposition, including applying to subject in need With the compound of any one of claim 1-31 of effective dose.

The administration of the method for 38. any one of claim 34-37, the wherein compound does not substantially produce unfavorable nerve essence The impact of refreshing disease.

The method of 39. any one of claim 34-39, the administration of the wherein compound causes in brain in Cmax and blood plasma most The ratio of big concentration is less than 0.1.